SU1577700A3 - Method of obtaining 9-oxime derivatives of perythromycin a - Google Patents

Abstract

A method for the selective methylation of a hydroxy group at the 6-position of an erythromycin A derivative comprises converting an erythromycin A derivative into an erythromycin A 9-oxime derivative, and reacting the resulting erythromycin A 9-oxime derivative with a methylating agent.

Description

This invention relates to the chemistry of antibiotics, specifically to a method for producing novel 9-oxime derivatives of erythromycin A of the general formula

-IN 3

Rlon l

9H3OSN3

 ss-Len

CH3

nsSn5sG6.

about

about

about

hgon

Н3СО СК3

s

(I)

de R (- lower 0 ,, - Cd-alkyl, benzyl group, unsubstituted or substituted by methoxy group,

25

a nitro group, one or two halogen atoms, a naphthyl methyl group, a methyl thiomethyl group, a 1,2,2-trichloroethoxymethyl group, a benzyloxymethyl group, a benzhydryl group; R is a hydrogen atom or a benzyloxycarbonyl group, provided that R2 is not a hydrogen atom when R 30 is methyl intermediates in the synthesis of 6-0-methyerythromycins used as antiseptics or intermediates for their synthesis . The purpose of the invention is the development of new 9-oxime derivatives of erythromycin A, the use of which in the synthesis will increase the selectivity of producing 6-0-methyl derivatives of erythromycin. Example 1. Preparation of 2 tO, 3-N-bis (benzyloxycarbonyl) -Y dimethyl-erythromycin A 9-oxime.45

To 300 ml of dry methanol 49.4 g (0.05 mol) g of 2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A, 17.4 g (0.25 mol) of hydrochloride hydroxylamine and 18.73 g of JQ (0.275 mol) of imidazole and the mixture is stirred at room temperature for 3 days. Most of the solvent was evaporated, the residue was poured into 700 ml of saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with twice 500 ml of ethyl acetate. These ethyl acetate layers are combined, washed three times with 300 ml of saturated

0

five

five

0 0 35 40 45

Jq -

an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solution is evaporated to recrystallize from a mixture of chloroform and petroleum ether, in order to obtain 34 $ 6 g (69.3%) of the desired compound. M.p. 149-151 ° C.

Calculated,%: C 62.26; H 7.84; N 2.79.

C52.Hr8N2G, T

Found,%: C 61.97; H, 7.58; N, 2.72.

Example 2. Getting 2 / -0,3 / - N-bis (benzyloxycarbonyl) -K-dimethyl-erythromycin A (meth-nitrobenzyl) -.

In 30 ml of acetone, 5 g (0.005 mol), 2-0.3 NI-bis (benzyloxycarbonyl) -N-demethylerythromycin A 9-oxime, 0.94 g (0.0054 mol) of metinitrobenzyl chloride are dissolved and added 0.362 g (0.0054 mol) of 85% powdered potassium hydroxide powder, the mixture is stirred for 2 hours.

The solvent is evaporated under reduced pressure. To the residue was added 100 ml of a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted three times with 150 ml of ethyl acetate. The layers of organic solvent were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent is evaporated, and the crude product obtained in this way is purified using silica gel column (distribution) chromatography (C-200 Wako gel, manufactured by Juniac Cl.). A mixture of benzene and ethyl acetate in the ratio of 3: 1 is used as a solvent for elution with i 4.79 g (83.3%) of the desired compound, which is then subjected to recrystallization from a mixture of ethyl acetate and n-hexane. M.p. 108 ° C.

Using a similar technology, the following compounds are obtained:

2-0.3 -Y-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-methyloxime), m.p. 118-1210G;

2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-ethyloxime), m.p. 112-114 ° C;

2-0.3 -N-bis (beneroyloxycarbonyl) - N-demethylerythromycin A 9- (0-propylene), so pl. 103-105 ° C;

2 0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-para-methoxybenzyloxy), m.p., 100-102 C;

2 0.3 -N-bis (benzyloxycarbonyl) -N-demrtilelerythromycin A (meta-chlorobenzyl) oxime, m.p. 99-100 ° C;

2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A (1-naphthylmethyl) oxime, m.p. 187-189 ° C.

Example 3. Preparation of 3-N-bis (benzyloxycarbonyl) -C-demethyl-erythromycin A (para-bromobenzyl) OKCHMj.

20.0 g (0.02 mol) of 2-0.3 -N-bis (benzyloxycarbonyl) -11-demethyl erythromycin A 9-oxime, 6.0 g (0.024 mol) of p-bromobenzyl bromide are dissolved in 80 ml of acetone and 1.23 g (0.0186 mol) of 85% potassium hydroxide powder was added and the mixture was stirred for 2 hours at room temperature.

According to the procedure of Example 2, a crude product is obtained, which is then recrystallized from a mixture of diethyl ether and petroleum ether to give 21.3 (91.0%) of the desired compound. M.p. 100-102 ° C.

Using a similar technology, the following compounds are obtained:

2-0.3 -N-bis (benzyloxycarbonyl) - N-demethylerythromycin A 9-Q) - (H-n-pyloxime), so pl. 109-111 ° C;

2 -O, 3 -N-bis- (benzyloxycarbonyl) -N-demethylery thromycin A (p-chlorobenzyl) oxime3, mp. 127-130 ° C;

2 -0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A (2,4-dichlorobenzyl) oxime, m.p. 94.5-96 ° C;

2-0.3 -N-bis (benzyloxycarbonyl) -N-demethylerythromycin A 9-Ј- (p-nitrobenzyl) oxime |, so pl. 119-121 C.

Example 4. Preparation of 2-0.3 - N-bis (benzyloxycarbonyl) -M-dimethyl-erythromycin A (methoxymethyl) oxime.

1 g (0.001 mol) of 2-0.3 -H-bis- (benzyloxycarbonyl) -1 1-demethyl-erythromycin A 9-oxime and 0.1 ml (0.0012 mol) of methyl chloromethyl are dissolved in 20 ml of tetrahydrofuran. - L-ether, 68 mg (0.0012 mol) of 50% sodium hydride are added and the mixture is stirred at room temperature for 15 minutes.

Upon completion of the reaction, the mixture is diluted with 100 ml of ethyl acetate and 100 ml of water is added to the contents. The organic layer is separated; wash alternately with saturated aqueous sodium bicarbonate and water

sodium chloride solution and dried over anhydrous magnesium sulphate. After evaporation of the solvent, the crude product thus obtained is purified using silica gel column chromatography (Wacogel C-200, a mixture of benzene and acetone and in a ratio of 10: 1-5; 1 as a solvent for elution), and is recrystallized from acetone and n-hexane to give 590 mg (56.7%) of the title compound as crystals. M.p. 101-104 S.

IR (): 2420, 1745, 1735, 1700.

NMR (SPS13) Ј: 344 (3N, 6-OCH3K) The following compounds were prepared in a similar manner:

0 2 -0,3 -N-bis (benzyloxycarbonyl) - N-demethylerythromycin A (methylthiomethyl) oxime, so pl. 101-104 ° C;

2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A (2.2.25 trichloroethoxymethyl) oxime), mp. 108-lll ° C; p

21-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A (benzyl symethyl) oxime |, m.p. 122-124 S.

0 Example 5. Preparation of 2-0.3 -N-bis (benzyloxycarbonyl) -demetnl-erythromycin A 9- (0 benzyloxyma).

20.06 g (0.02 mol), 2-0.3 -N-bis (benzyloxycarbonyl) -M-demethyl-erythromycin A 9-oxime, and 3.37 g (0.026 g) are dissolved in 159 ml of dry 1-dimethylformacide. mole) benzyl chloride, 1.25 g of Q (0.03 mol) of 60% sodium hydride is added to the contents and the mixture is stirred for 1 hour. The reaction solution is poured onto 600 ml of a saturated aqueous solution of sodium bicarbonate. The mixture is extracted once with 300 ml of ethyl acetate, and a second time with 200 ml of the same solvent. The ethyl acetate layer was washed three times with 300 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent is evaporated and the crude product obtained in this way is purified using silica gel column chromatography Art. 7734 from Merck Co., a mixture of ethyl acetate and n-hexane in a ratio of 1: 2-1: 1 as a solvent for elution), to give 17.92 g (80.2%) of the title compound, which

0

five

then recrystallized from ethyl acetate and petroleum ether.

Calculated,%: C 64.82; H 7.74; N 2.56.

Cs, He4NzO, 4

Found,%: C 64.41; H 7.56; No. 2.64.

 U ya

(cm): 3450, 1750,

ten

C-200 gel, a mixture of ethyl acetate and n-hex San 2: 1 as eluent). The fractions characterized by the results of chromatography in a thin layer with the value RY 0.21 (thin layer plate silica gel, 60 F 254, Merck Co., a mixture of chloroform and methanol in a ratio of 20: 1 as a developing agent) are collected and evaporated to dryness under reduced pressure to obtain 3.0 g of the same substance, which is the target compound in example 1

15

Kf ha

20

thirty

IR J max 1735, 1700.

NMR (C1) C1, Ј: 4.96-5.24 (6H), 7.20-7.50 (15H).

13C NMR (CDC1,): 26.6 (C8), 171.1 (C), 33.1 (C10), 18.5 (8-CH,), 14.6 (Yu-CH3). M.p. 105-107 ° C.

Using a similar technology, the following compounds are obtained:

2 -0.3 -C-bis (benzyloxycarbonyl) - N-demethylerythromycin A (9-benzhyd rioxime);

2 -0, (2 methoxyethoxy) methyl-oxime, so pl. 99-104 S.

Example .6. Preparation of 2-0, 3 H-bis (benzyloxycarbonyl) -C-demethylerythromycin A (ortho-chlorobenzyl) -25 of the compound from Example 1 in oxime chloroform.

13 g (0.013 mol) of 2; -0.3-bis- (benzyloxycarbonyl) -Y-demethylerythromycin A 9-oxime is dissolved in 60 ml of C-M-dimethylformamide and 2.30 g (0.014 mol) of ortho-chlorobenzyl chloride and 0.941 g (0.014 mol) of 85% sodium hydrate as a powder with ice cooling and the mixture is stirred for 2 hours.

After completion of the reaction, the mixture is poured into 400 ml of water, and the precipitated crystals are filtered and washed with water. Then the crystals are additionally washed with 10 ml of a 10% aqueous solution of ethanol and dried to obtain 14.02 g (96.1%) of the target compound as crystals, which are subjected to recrystallization from a mixture of ethyl acetate and n-hexane. M.p. 1P-113 ° C.

IR If Telte (): 3420, 1745, 1735. NMR (CDC1,) and: 7.23-7.46 (14H). Example 7. Preparation of 2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9-oxime (another oxime isomer of the compound obtained in Example 1).

The mother liquor obtained by recrystallization in Example 1 was evaporated to dryness under reduced pressure, and the residue thus obtained was separated using silica gel column chromatography (WacoPale, this fraction with a value of 0.12 was collected and evaporated under reduced pressure to obtain 540 mg The title compound is a white foam. mp. 115-130 ° C.

Using thin layer chromatography, it was found that part of this compound is isomerized to the target

or by heating. In addition, this compound is difficult to purify by recrystallization, and this compound does not have any specific melting point.

Calculated,%: C 62.26; H 7.84; 2.70.

C5lH68N2 ° r

Found,%: C 61.95; H 7.90;

2.85. (

IC-PEDS (cm): 3650-3360; 1750;

N

N

40

1735; 1700

Example 8. Preparation of 2-0.3 M bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-benzyloxime) (another oxime isomer of the title compound from Example 5).

250 mg (0.00025 mol) of 45 2-0.3 -Y-bis (benzyloxycarbonyl) -H demethyl-erythromycin A 9-oxime, another oxime isomer of the target compound from of example 1, prepared according to example 7, and 65 ml (0.0005 mol) of benzyl chloride, 25 ml (0.0003 mol) of 85% potassium hydroxide in powder form are added to the contents and the mixture is stirred with ice cooling in for 2 h. The mixture is poured into 10 ml of water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sulfate and m After evaporation of the solvent STI polu50

55

gel C-200, a mixture of ethyl acetate and n-hex-San in a ratio of 2: 1 as a solvent for elution). The fractions characterized by the results of chromatography in a thin layer with the value RY 0.21 (thin layer plate silica gel, 60 F 254, Merck Co., a mixture of chloroform and methanol in a ratio of 20: 1 as a developing agent) are collected and evaporated to dryness under reduced pressure to obtain 3.0 g of the same substance, which is the target compound in Example 1.

Kf ha

compounds of example 1 in chloroform

After this, fractions with a value of 0.12 are collected and the mixture is evaporated to reduced pressure to obtain 540 mg of the title compound as a white foam. M.p. 115-130 ° C.

Using thin layer chromatography, it was found that part of this compound is isomerized to the target

0

5 compounds of example 1 in chloroform

or by heating. In addition, this compound is difficult to purify by recrystallization and this compound does not have any specific melting point.

Calculated,%: C 62.26; H 7.84; 2.70.

C5lH68N2 ° r

Found,%: C 61.95; H 7.90;

2.85. (

IC-PEDS (cm): 3650-3360; 1750;

N

N

0

1735; 1700

Example 8. Preparation of 2-0.3 - M-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-benzyloxime) (another oxime isomer of the title compound from Example 5).

250 mg (0.00025 mol) of 5 2-0.3 -Y-bis (benzyloxycarbonyl) -H demethyl-erythromycin A 9-oxime, another oxime isomer of the target compound from of example 1, prepared according to example 7, and 65 ml (0.0005 mol) of benzyl chloride, 25 ml (0.0003 mol) of 85% potassium hydroxide in powder form are added to the contents and the mixture is stirred with ice cooling in for 2 h. The mixture is poured into 10 ml of water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sulfate and ma rot After evaporation of the solvent

five

The crude product in this way is separated using silica gel column chromatography (V-cogel C-200, a mixture of benzene and acetone in a 6: 1 ratio as elution solvent).

The fractions characterized by the results of chromatography in a thin layer with a Rf value of 0.57 (thin layer plate 60 F 254, Merck Co., a mixture of benzene and acetone in the ratio 3: 1 as a developing solvent) are collected and evaporated to dryness with

one

70010

350 ml of ethyl acetate. The ethyl acetate layers are combined, washed twice with 300 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product obtained in this way is purified using silica gel column chromatography (W-cogel C-200, a mixture of ethyl acetate and n-hexane in a ratio of 1: 2-3.1 as eluent) to give 8.6% g (67.3%) of the target compound, which is then redrawn

20

25

obtaining 50 mg of substance; - with the target compound of example 5.

Then the fractions with a Rr value of 0.48 are collected and evaporated to dryness under reduced pressure to obtain 150 mg of the target compound, which is then recrystallized from diethyl ether.

NMR (CDC13): 34.4 (C &), 168.9 (C,), 35.7 (C10), 19.7 (8-CH3), 11.3 (10-СНЭ). M.p. 144-147 ° C.

Using chromatography on a thin layer, it was found that this compound does not change either in chloroform or as a result of heating.

Example 9.30

a) Preparation of 3K-benzyloxycarbonyl-K-demethylerythromycin A. 29 g (0.04 mol) of N-demethylerythromycin A are dissolved in 250 ml of methylene chloride.

and to the contents were added 27.8 ml (0.2 mol) of triethylamine and 7.5 g (0.044 mol) of benzyloxycarbonyl with ice cooling. The mixture was stirred at 0-5 ° C for 5 hours and evaporated to approximately 50 ml. 800 ml of water was added to the mixture, and the precipitated crystals were filtered to obtain 20 g of the desired compound, which was then recrystallized from a mixture of ethyl acetate and n-hexane. M.p. 157-158 ° C.

b) Preparation of 3-N-benzyloxycarbonyl-M-demethyl-erythromycin A 9-hydroxyl. 12.55 g (0.0147 mol) of semi-35 are added to 7.5 ml of anhydrous methanol.

40

45

Talsed from a mixture of ethyl acetate and petroleum ether. M.p. 169.5-170.5 ° C.

Example 10. Preparation of 3-N-benzyloxycarbonyl-M-demethyl-erythromycin A 9- (0-benzyloxyma).

4.79 g (0.0055 mol) of 3-M-benzyloxycarbonyl-H-demethyl-erythromycin A 9-oxime and 1.4 g (0.011 mol) of benzyl chloride are dissolved in 30 ml of M, M-dimethylformamide, and benzyl chloride is added to the content 0.55 g (0.008 mol) of 85% potassium hydroxide as powder using ice cooling and the mixture is stirred for 2 hours.

The mixture was subjected to the same treatment as in Example 6. The crude product thus obtained was purified using silica gel column chromatography (C-200 Wacogel, a mixture of benzene and acetone, in a 40: 1 ratio as elution solvent) to give 4, 55 g (86.0%) of the desired compound, which is then recrystallized from isopropyl alcohol. M.p. 110-113 ° C.

Example 11. Preparation of erythromycin A 9-Ј0- (ortho-chlorobenzyl) oxy-MaJ.

1.498 g (0.002 mol) erythromycin A 9-oxime, 354 mg (0.0022 mol) of ortho-chlorobenzyl chloride and 168 mg (0.0025 mol) of 85% potassium hydroxide as a powder in 100 ml, N, N - dimethylformamide is subjected to combined Z-M-benzyloxycarbonyl-M-de-ZO stirring at room temmethyl erythromycin A, 5, 1 1 g (0.073 mol) of hydroxylamine hydrochloride to 5.5 g (0.08 mol) imidazole and the mixture is stirred at room temperature for 52 hours. Most of the solvent 55 is evaporated, the residue is poured into 200 ml of a saturated aqueous solution of sodium bicarbonate and three times ragiruyut

0

five

-

0

five

0

five

Talsed from a mixture of ethyl acetate and petroleum ether. M.p. 169.5-170.5 ° C.

Example 10. Preparation of 3-N-benzyloxycarbonyl-M-demethyl-erythromycin A 9- (0-benzyloxyma).

4.79 g (0.0055 mol) of 3-M-benzyloxycarbonyl-H-demethyl-erythromycin A 9-oxime and 1.4 g (0.011 mol) of benzyl chloride are dissolved in 30 ml of M, M-dimethylformamide, and benzyl chloride is added to the content 0.55 g (0.008 mol) of 85% potassium hydroxide as powder using ice cooling and the mixture is stirred for 2 hours.

The mixture was subjected to the same treatment as in Example 6. The crude product thus obtained was purified using silica gel column chromatography (C-200 Wacogel, a mixture of benzene and acetone, in a 40: 1 ratio as elution solvent) to give 4, 55 g (86.0%) of the desired compound, which is then recrystallized from isopropyl alcohol. M.p. 110-113 ° C.

Example 11. Preparation of erythromycin A 9-Ј0- (ortho-chlorobenzyl) oxy-MaJ.

1.498 g (0.002 mol) erythromycin A 9-oxime, 354 mg (0.0022 mol) of ortho-chlorobenzyl chloride and 168 mg (0.0025 mol) of 85% potassium hydroxide as a powder in 100 ml, N, N - dimethylformamide is combined for 1.5 hours to accelerate the reaction. After that, the mixture is poured into 500 ml of ice water and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent is evaporated and the residue is subjected

Н1

purification using silica gel column chromatography (Wacogel C-200, ethyl acetate as eluent) and recrystallized

Tallized from n-hexane to give 1.562 g (89.3%) of the title compound. M.p. 114-117 ° C.

To a mixture of 5.14 ml (0.0057 mol) of the compound thus obtained and 5.77 g (0.68 mol) of sodium bicarbonate in 8.5 ml of dioxane was added dropwise 8.14 ml (0.057 mol) of benzyloxycarbonyl chloride with stirring at 55-65 ° C. The mixture was stirred at 65 ° C for 1 hour. After completion of the reaction, 10 ml of dichloromethane was added to the reaction mixture. Received. the mixture is filtered and the filtrate is diluted with 80 ml of n-hexane to give 5.92 g (91.6%) of 2-0, N-bis (benzyloxycarbonyl) -M-demethyl-erythromycin A (ortho-chlorobenzyl) oxime in crystalline form. This compound is identical to the compound obtained in Example 6 for the data on the melting point of the insoluble residue on NMR.

Example 12, Preparation of 6-0-methyl-2-0.3-M-bis (benzyloxycarbonyl) -M-demethylerythromycin A (0-methyloxime.

1.02 g (0.001 mol) of 2 g-0.3-M-bis (benzyloxycarbonyl) -N-dimethylerythromycin A 9- (0 methyl oxime) is dissolved in 12 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1: 1 ratio). . 341 mg (0.024 mol) of methyl iodide and 100 mg (0.0015 mol) of 85% potassium hydroxide in powder form are added to the solution and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of a saturated aqueous solution of sodium bicarbonate and the mixture is subjected to extraction once with 100 ml of ethyl acetate, and another time with 50 ml of the same solvent. The ethyl acetate layer was washed three times with 100 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent is evaporated under reduced pressure, and the residue thus obtained is purified by using silica gel column chromatography (Wacogel C-200, a mixture of j ethyl acetate and n-hexane in a ratio of 1: 1 as a solvent for

12

elution) to obtain 0.82 g (79.1%) of the title compound as a white foam.

Calculated,%: C, 62.89; H 8.02; N 2.72.

C64H8 Nz ° 7

Found,%: C 62.48; H 7.93; N2,65

IR | f max (cm): 3500-3350, 1750 1735, 1700.

PMR (SOSTS) b: 3.50 (3N, 6-OCH,), 3.79 (3N, N-OCH,).

NMR f3C (CDC1JU: 50.6 (6-OCH 3), 69.4 (N-OCHj).

Example 13. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl N-methyl erythromycin A 9- (0-ethyloxy).

According to the technologist of Example 12 and using 1.028 g (0.001 mol) 2- 0.3 -N-bis (benzyloxycarbonyl) -P-de-methyl-erythromycin A 9- (0-ethylrxime), 341 mg (0.002 mol) of methyl iodide and 100 mg (0.0015 mol) of 85% potassium hydroxide in powder form in 12 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1: 1) give 1.05 g of crude product, which is then recrystallized from a mixture of diethyl ether and n hexane to obtain 0, Y5 g (81.7%) of the target compound in the form of crystals:

IR (): 3500-3350, 1735,

NMR (CDC13): 3.03, 3.04 (3N, 6OCH3). M.p. 105-108 ° C.

Calculated,%: C, 63.20; H 8.10; N 2.68.

C55H84N2.

Found,%: C 63.23; H 7.84;

N 2.72.

CK yKf (): 3500-3350, 1735 1700.

NMR (CDC15) 64: 3.03, 3.04 (3N, 6OCHN).

13 C NMR (CDC13) &: 50.6 (6-OCH3).

Example 14. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -Y-demethylerythromycin A 9-JJ3- (n-propyl) oxime.

The technology is similar to example 12, taking 1.042 g (0.001 mol) of 2- 0.3 -N-bis (benzyloxycarbonyl) -Y-demethyl-erythromycin A (n-propyl hydroxymac.

370 mg (0, mol) of methyl iodide and 100 mg (0.0015 mol) of 85% potassium hydroxide as powder in

31

12 ml of a mixture of DMSO and tetrahydrofuran (1: 1 ratio) to accelerate the reaction, obtain 1.13 g of crude product, which is then purified using the same silica gel column chromatography as in Example 12, to give 0.52 g (49.2%) of the title compound as a white foam.

Calculated,%: C 63.49; H 8.18; N 2.65.

20

C56H86N2- ° f7

Found,%: C 63.53; H 8.10; N 2.75. .ick (): 3500-3350, 1748,, 1735, 1700.

NMR (CDC13U: 3.03, 3.04 (3N, 6-OCH3).

3C NMR (CDClj) S: 50.7 (6-OCH,).

Example 15. Preparation of 6-0-methyl-2-0, 3-H-bis (benzyloxycarbonyl) -M-demethylerythromycin A 9- (0-isopropyloxime).

The reaction is carried out in accordance with the technology of Example 12 and using 0.44 g (0.0004 mol) 21-0, 3H-bis- (benzyloxycarbonyl) -M-demethylerythromycin A 9- (0-isopropyloxime), 144 mg (0.001 mol) of methyl iodide and 41.8 mg (0.0006%) of 85% potassium hydroxide as a powder in 6 ml of a mixture of DM80 and tetrahydrofuran (in the ratio 1: 1). In accordance with known technology and followed by purification based on the use of the same silica gel column chromatography used in Example 12, 0.36 g (80.9%) of the title compound is obtained as white foam.

Calculated,%: C 63.49; H 8.18; N 2.65.

C56H86N ° 17

Found,%: C, 63.39; H, 7.86; N, 2.72.

m) gp

(): 3500-3350, 1748,

W J mchs-1730, 1700.

NMR (CDC13): 3.03, 3.04 (AH,

6-och d). 13,

Calculated,%: C, 62.25; H 7.98; N 2.64.

C55H84N20 (a

Found,%: C 62.25; H 7.99; N 2.75.

NMR (CDCl3) o: 3.07 (6-OCH,). NMR (CDC15) S: 50.7 (6-OCH3). Example 17. Preparation of 6-0-metsht-2 -0.3 -M-bis (benzyloxycarbonyl) -M-demethylerythromycin A 9-Ј0- (methylthiomethyl) oxime.

Analogous to example 12 using 230 mg (0.0002 mol) 2-0.3-25 N-bis (benzyloxycarbonyl) -M-demethyl-erythromycin A 9-0-methylthiomethyl) oxime, 98 mg (0.0007 mol) methyl iodide and 20 mg (0.0003 mol) of 85% potassium hydroxide in powder form in 4 ml of a mixture of DM80 and tetrahydrofuran (1: 1 ratio) give 230 mg of the crude product, which is then purified using silica gel column chromatography (Wacogel C-200, methylene chloride as eluent) to give 98 mg (42.0%) of the solid compound as a white foam color.

NMR (CDC13) 8: 2.23 (3N, -CH3), 3.07 (3N 6-OCH,), 5.08 (2H, -OCE.S-)

IR UKCD (cm-): 3500-3350,1740, 1730, 1695.

Example 18. Getting 6-0-ME30

35

40

tyl-2 -O, 3 -N-bis (.benzyloxycarbo4 nyl) -K-demethylerythromycin A 9 (0-benzyloxyma).

 With NMR (CDC13) 8: 50.7 (6-OCH). In accordance with the technology described in Example 16. The preparation of 6-0-metabolic example of Example 12 was carried out with the reactivity of 2 -0, 3 -H-bis (benzyloxycarbo-D1110 using 1.09 g (0.001 mol)

Nile) -K-dimethyl erythromycin A (me-502; -0.3 -N-bis (benzotloxycarbonyl) -Ntoxymethyl) -oxime D, demethyl erythromycin A 9- (0-benzyloxyK 10 ml of a mixture of DMO and tetrahydro); 341 g ( 0.0024 mol) iodide furan (in a 1: 1 ratio) 1.0 g (0.001 mol) 2-0.3 -M-bis- (benzyloxycarbonyl) -I-demethyl-eryth-55 romicin A (methoxymethyl) oxime D is added. , 320 mg (0.0023 mol) of methyl iodide and 95 mg (0.0014 mol)

methyl and 99 mg (0.0015 mol) of 85% potassium hydroxide in powder form in 12 ml of a mixture of DM50 and tetrahydrofuran (1: 1 ratio). During the subsequent purification carried out using silica gel column chromatograph14

0

0

85% potassium hydroxide in powder form and stirred at room temperature for 45 minutes to carry out the reaction. Analogously to Example 12, a crude product is obtained, which is then recrystallized from a mixture of acetone and n-hexane, to give 705 mg (69.6%) of the title compound as crystals. M.p. 197-199 ° C.

Calculated,%: C, 62.25; H 7.98; N 2.64.

C55H84N20 (a

Found,%: C 62.25; H 7.99; N 2.75.

NMR (CDCl3) o: 3.07 (6-OCH,). NMR (CDC15) S: 50.7 (6-OCH3). Example 17. Preparation of 6-0-metsht-2 -0.3 -M-bis (benzyloxycarbonyl) -M-demethylerythromycin A 9-Ј0- (methylthiomethyl) oxime.

Analogous to example 12 using 230 mg (0.0002 mol) 2-0.3-5 N-bis (benzyloxycarbonyl) -M-demethyl-erythromycin A 9-0-methylthiomethyl) oxime, 98 mg (0.0007 mol) methyl iodide and 20 mg (0.0003 mol) of 85% potassium hydroxide in powder form in 4 ml of a mixture of DM80 and tetrahydrofuran (1: 1 ratio) give 230 mg of the crude product, which is then purified using silica gel column chromatography (Wacogel C-200, methylene chloride as eluent) to give 98 mg (42.0%) of the solid compound as a white foam colors.

NMR (CDC13) 8: 2.23 (3N, -CH3), 3.07 (3N 6-OCH), 5.08 (2H, -OCE.S-).

IR UKCD (cm-): 3500-3350,1740, 1730, 1695.

Example 18. Getting 6-0-me0

five

0

tyl-2-O, 3 -N-bis (.benzyloxycarbonyl) -K-demethyl-erythromycin A 9 (0-ba

ma), 341 g (0.0024 mol) iodide

methyl and 99 mg (0.0015 mol) of 85% potassium hydroxide in powder form in 12 ml of a mixture of DM50 and tetrahydrofuran (1: 1 ratio). For subsequent purification using silica gel column chromatography, 830 mg (75.5%) of the title compound are obtained as a white foam, which is then recrystallized from a mixture of diethyl ether and petroleum ether. M.p. 154.5-156 ° C.

Calculated,%: C 65.08; H 7.83; N 2.53.

C6H86N2- ° ir

Found,%: C 64.76; H 7.83;

No. 2.53.

i In Maca Sem 1): 3400, 1750, 1735, 1/00.

NM (CDC13) Ј: 2.95 (AH, 6-HOS,). 1E

 With NMR (): 26.4 (C8), 1 / 2,1 (C 4), 33.0 (C, 0), 18.6 (8-CH3), 15.3 (10-CH3).

Example 19. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) N-demethyl-erythromycin A (para-1 hydroxybenzyl) oxime.

5, bg (0.005 yl) 2-0, g -I-bis- (benzyloxycarbonyl) -N-demethylerythromycin A (para-methoxybenzyloxy), 1.7 g (0.012 mol) of methyl iodide and 995 mg (0.015 mol ) 85% potassium hydroxide in powder form in 60 ml of DMZo and tetrahydrofuran (reagent ratio 1: 1-5: 0.8-3) is stirred for 3.5 hours to accelerate the reaction. According to the technology of Example 12, approximately 6 g of crude product is obtained, which is then subjected to purification using silica gel column chromatography (W-Kogel C-200, a mixture of ethyl acetate and n-hexane in a 1: 2 ratio as elution solvent). yielding 4.3 g (75.8%) of the title compound as a white foam

go color. &

(cm): 3450, 1745, 1730,

IR / f for xc 1700.

NMR (CDC1}) Ј: 2.99 (3N, 6-OCH 3), 3.80 (3N, F-OCH,).

 NMR (CDC13) (: 50.6 (H) 55.2 (F-CH3).

Calculated,%: C 64.41; H 7.80; N 2.46.

Found,%: C 63.67; H 7.67j.

N 2.46.

Example 20. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -C-dimethylerythromycin A (para-chlorobenzyloxyma) J.

To 100 ml of a mixture of DMZO and tetrahydrofuran (1: 1 ratio) is added

five

five

8.3 g (0.007 mol) 2-0.3 -M-bis- (benzyloxycarbonyl) -N-demethylerythromycin A (para-chlorobenzyloxy-am), 2.5 g (0, 0175 mol) of methyl iodide and 730 mg (0.011 mol) of 85% potassium hydroxide in powder form and the mixture is stirred at room temperature for 2 hours to accelerate the reaction. According to the technology of Example 12, a crude product is obtained, which is then purified using silica gel column chromatography (W-Kogel C-200, a mixture of benzene and acetone in a ratio of 50: 1-25: 1 as eluent) to obtain 7.5 g (89.3%) of the title compound as a white foam.

Calculated,%: C 63.12; H 7.50; N 2.45.

C60Hg ClN40.7

Found,%: C 62.96; H 7.40; N 2.49.

0

five

IR at (cm): 3500-3350, 1747, 1728, 1700.

NMR (CDCl3) d: 3.01, 3.03 (3N, 6-och j).

H5C NMR (AHSC) #: 50.7 (6-OCH3).

Example 21. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9-Ј- (meth-chlorobenzyloxy).

1.12 g (0.001 mol) 2 (-0.3 (-N-bis- (benzyloxycarbonyl) -K-demethylerythromycin A (meth chlorobenzyl) oxy-MaJ, 320 g (0.00225 mol) iodide metal and 73 mg (0.0011 mol) of 85% potassium hydroxide in powder form in 12 ml of a mixture of DM50 and tetrahydrofuran (1: 1) are mixed together at room temperature for 2 hours. According to the method of Example 16 - a crude product is obtained, which is then purified using silica gel column chromatography (fakogel C-200, methylene chloride as a solvent for elution) to obtain 1.13 g (99.7%) c of the title compound in the form of crystals. mp. 86-94 ° C.

0

0

7.50;

C, 63.12; H

62.96; H 7.47;

N

2.43.

Example 22. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbo 17

Nile) -M-demethyl-erythromycin A (ortho-xporbenzyloxy) 1.

In 50 ml of H, M-demethylformamide, 13 g (0.01115 mol) of 2-0 is dissolved, 3-M-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9-O- (ortho-chlorobenzyl) -oxime, after 2.1 g (0.015 mol) of methyl iodide and 0.827 g (0.0125 mol) of 85% hydrate of potassium oxide in the form of powder were added during ice cooling, and the mixture was stirred for 5 h. After completion of the reaction, the mixture is poured into 400 ml of water, the separated crystals are filtered off, washed with 100 ml of 10% aqueous ethanol and dried. The crude product thus obtained is recrystallized from isopropyl alcohol to give JQ iO, 27 g (78.1%) of the title compound as crystals. M.p. 191-193 c.

Calculated,%: C 63.12; H 7.50; N 2.45.

С60НВ5С11Ц01725

Found,%: C 63.10; H 7.39; N 2.52.

Example 23. Preparation of 6-0-me-, 3 -N-bis (benzyloxycarbonyl) -I-demethyl-erythromycin A 9-Ј0 (para-30 p-bromobeneyl) oxime.

11.72 g (0.01 mol) 2-0, 3 —Y-bis- (benzyloxycarbonyl) -M-demethyl-erythromycin A 9-Gr- (para-bromobenzyloxy), 3.41 g (0.024 mol) of methyl iodide and 990 mg (0.015 mol) of 85% potassium hydroxide in powder form in 120 ml of DMZO-dimethyl and tetrahydrofuran (in the ratio l: l) are mixed together at room temperature-, re for 1 hour. According to the technology of example 12 a crude product is obtained, which is then purified using silica gel column chromatography (Wacogel C-200, mixture of ethyl acetate and n-hexane in a 1: 2 ratio as solvent eluted Rovani) to obtain 10.45 g (88.1%) Spruce compound as a white-foam th color. Mp 98-103 ° C.

Calculated,%: C 6Q, 75; H 7.22; N 2.39.

С60Нв5ВгНаО, 7

Found,%: C 60.92; H 7.02; N 2.37.

IR) f ° 1595. ake

NMR (CBC13): 2.99-3.02 (3N, 6-OCH3).

50

(): 3400, 1745, 1730, 55

77

tQ jc jq

25

thirty

", D

50

55

/ 0018

43C NMR (CDC1,) $: 50.7.

Example 24 Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl J-N-demethyl erythromycin A 9-0) - (2,4-dichlorobenzyl) oxime.

To 48 ml of a mixture of DM50 and tetrahydrofuran (1: 1) was added 4.044 (0.0035 mol) 2G-0.3 -N-bis- (benzyloxycarbopyl) -Y-demethylerythromycin A (2, 4-dichlorobenzyl) hydroxy-MaJ, 1.33 g (0.009 mol) of methyl iodide and 380 mg (0.005 mol) of 85% potassium hydroxide as a powder, and the mixture is stirred to carry out the reaction. After reacting for 4.5 hours, the reaction mass is treated according to the method of Example 1, a crude product is obtained, which is then recrystallized from a mixture of diethyl ether and n-hexane to give 3.5 g (85.6%) of the desired compound as crystals. M.p. 180-181 ° C.

Calculated,%: C, 61.27; H 7.20; N 2.38.

C6on84C1 N20i7

Found,%: C 61.34; H 7.04;

N 2.45.

NMR (CO1E) §: 3.00, 3.01 (3N, 6-OCHs), 5.07, 5.09 (2H, -CH2-F).

Example 25. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -C-demethylerythromycin A (benzhydryl) oxime |.

940 mg (0.0008 mol) 2 (-0, g-M-bis (benzyloxycarbonyl) -N-demethyl-erythromycin A 9- (0-benzhydrolox) are reacted with 350 mg (0.0025 mol) of methyl iodide and 92 mg (0.0013 mol) of 85% potassium hydroxide in 12 ml of a mixture of sulfoxide of dimethyl and tetrahydrofuran (1: 1 ratio) and stirred for 1 hour. As a result of the treatment of example 12, a crude product is obtained which is then subjected to purification using silica gel column chromatography (Wacogel C-200, a mixture of ethyl acetag and n-hexane in a 1: 2 ratio as solvent for the elur Vani) to give 620 mg (65.2%) of the title compound.

IR J run (cm -1): 3500-3350, 1745, 1730, 1700.

NMR (CBC1E) Ј: 2.93, 2.99 (3N, 6-OCH,).

With NMR (SOS13): 50.7.

ten

Example 26. Preparation of 6-0-me-, 3 -N-bis (benzyloxycarbonyl) -N-demetsteritromitsin A 9 (0-trityloxyma).

To 4 ml of a mixture of DMZO and tetrahydrofuran (in a ratio of 1: 1J, 450 mg (0.00035 mol) of 2 -O, 3-N-bis- (benzoyloxycarbonyl) -demethyl erythromyromycin A 9- (0-trityloxime) are added , 123 mg (0.00086 mol) of methyl iodide and 30 mg (0.00045 mol) of 85% potassium hydroxide as a powder, and the mixture is mixed for 3 hours to carry out the reaction. Pa end of the reaction as a result The treatments in Example 12 receive a crude product, which is then purified using silica gel column chromatography (Wacogel C-200, methylene chloride as solvent eluant) to give 270 mg (59.3%) of the title compounds.

(cm 1): 3400, 1745, 1730,

K8p m to

IR (1700

NMR (CDCl3) ff: 2.98-3.01 (3N, 6-OCH3).

PRI me R 27. Preparation of 6-0-MeB I2 ml of a mixture of DMZO and tetrahydrofuran (1: 1 ratio) dissolve 1.1 g (0.001 mol) 2 / -0.3-I-bis ( benzyloxycarbonyl) -K-demethyl-erythromycin A (orthochloro benzyl) oxime; 0.23 ml (0.0024 mol) of dimethyl sulfate and 98 mg (0.0015 mol) of 85% potassium hydroxide in powder form are added to the contents; The mix is stirred at room temperature for a PO min to carry out the reaction. The treatment of Example 12 yields a crude product, which is then purified using silica gel column chromatography (Ref. 7734, Merck Co., methylene chloride as elution solvent) to obtain 760 mg of the same compound, which was obtained in Example 22

Example 29. Preparation of 6-0-methyl-2, 0.3 -N-bis (benz shtoxycarbenyl) H-demethylerythromycin A (meth-nitrobenzyl) oxime T.

2.97 g (0.0026 mol) 2-0 are dissolved in 20 ml of NjN-dimethylformamnda, 3–3 N-bis (benzyl sycron bonil) -N-demethyl-2-0, 3 -N-bis (benzyloxycarbonyl) -H-demethyl-erythromycin A 9- (0-benzo-erythromycin A (meta-nitrobenzyl) -yloxime). OximeP and added to the contents with

547 mg (0.0005 mol) 2; -0.3 -N-bis-ice cooling 0.444 g (0.0031 mol) of methyl iodide and 0.132 g are dissolved in 12 ml of a mixture of DMZO and tetrahydrofuran (in a 1: 1 ratio). (0.0031 mol) of 95% sodium hydroxide in powder form and the mixture is stirred with cooling for 1.5 hours to carry out the reaction. After completion of the reaction, 70 ml of ethyl acetate are added to the mixture, and the mixture is washed five times with 100 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the residue is purified 45 using silica gel column chromatography (C-200 Wacogel, 3: 1 mixture of benzene and ethyl acetate as elution solvent) to give 2.023 g (67.4%) of the target compound as a white foam colors.

(benzyloxycarbonyl) -H-demethyl-erythro

Mitsin A 9 (0-benzyloxime) and 1.37 g (0.009 mol) of methyl iodide, then 34 mg (0.00085 mol) of 60% sodium hydrate is added to the content and the mixture is stirred for 1 h to carry out the reaction .

As a result of the treatment according to the technology of Example 12, a crude product is obtained, which is then purified using silica gel column chromatography (Ref. 7734, Merck & Co., a mixture of ethyl acetate and n-hexane in a 1: 1 ratio as elution solvent) to give 383 mg (69.0%) of the desired compound.

This compound is identical to the compound obtained in Example 18B of the portion of the melting point, the insoluble residue and the NMR results.

Example 28. Preparation of 6-0-me-, 3 -N-bis (benzyloxycarbonyl) -N-demethylerythromycin A 9- (0- (ortho-chlorobenzyl) oxime.

n

1.1 g (0.001 mol) 2 / -0.3-And-bis (benzyloxycarbonyl) -K-demethylerythromycin A (orthochloro benzyl) are dissolved in I2 ml of a mixture of DMZO and tetrahydrofuran (1: 1 ratio). 0.23 ml (0.0024 mol) of dimethyl sulfate and 98 mg (0.0015 mol) of 85% potassium hydroxide in powder form are added to the content of oxime and mixed with stirring at room temperature for 40 minutes for the reaction. The treatment of Example 12 yields a crude product, which is then purified using silica gel column chromatography (Ref. 7734, Merck Co., methylene chloride as elution solvent) to obtain 760 mg of the same compound, which was obtained in Example 22

Example 29. Preparation of 6-0-methyl-2, 0.3 -N-bis (benz shtoksicarbo-5-nyl) H-demethylerythromycin A (meth-nitrobenzyl) oxime T.

2.97 g (0.0026 mol) 2-0, h-N-bis (benzyl sycron bonil) -N-demethyl erythromycin A (meta-nitrobenzyl)-hydroxympanum is dissolved in 20 ml of NjN-dimethylformaminda and added to the content are at

five

0

ice cooling 0.444 g (0.0031 mol) of methyl iodide and 0.132 g (0.0031 mol) of 95% sodium hydroxide powder and the mixture is stirred with cooling for 1.5 hours to carry out the reaction. After completion of the reaction, 70 ml of ethyl acetate are added to the mixture, and the mixture is washed five times with 100 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the residue is purified 5 using silica gel column chromatography (C-200 Wacogel, 3: 1 mixture of benzene and ethyl acetate as eluent) to obtain 2.023 g (67.4%) of the target compound as a white foam colors.

0

Kb

IR g (cm -1): 3420, 1745, 1738, 1700. MakC

NMR (CDCL3): 3.04, 3.05 (3N, 6-OCH3).

Example 30. Preparation of 6-0-methyl-Z -Q, 3 N-bis (benzyloxycarbonyl) -N-demethylerythromycin A (para-nitrobenzyl) oxime 7.

21

To 250 ml of a mixture of DM SO and tetrahydrofuran (in a 1: 1 ratio), 20.2 g (0.0155 mol) of 2-0.3 -N-bis- (benzyloxycarbonyl) -M-demethylacetate are added.

22 (cm-): 3360, 1755, 1733,

1690. My

NMR (CDC13) S: 3.01 (3N, 6-OCHj).

Example 32. Preparation of b-0-memicin A (p-nitrobenzyl) hydroxy-5-tyl-2-O, 3 (-N-bis (benzyloxycarbonate, then nyl) -M-demethylerythromycin A 9-. 0- (2methoxyethoxymethyl) oxime |.

8.58 g (0.008 mol) of 2-0.3 N-bis (benzyloxycarbonyl) -Y-demethyl-erythromycin A (2-methoxy-ethoxymethyl) oxime T and 5, are dissolved in 94 ml of a mixture of DMZO and 1,2 dimethyl-hydroxyethane. 37 g

3.02 g (0.021 mol) of methyl iodide and 1.41 g (0.021 mol) of 85% hydra10

This potassium oxide in the form of a cooled powder and the mixture is stirred for 1.5 hours to carry out the reaction. In addition, 2.52 g (0.018 mol) of methyl iodide and 0.586 g (0.0098 mol) of 85% hydro- 15 (O, O 6 mol) of 85% hydroxide potassium hydroxide in as powder and potassium as powder and the mixture is stirred for 2 hours. After completion of the reaction, 5.78 g (28.3%) of the desired compound, 20, is obtained in the form of a powder and a mixture of the changes are sewed for hours to carry out the Y (): 3400, 1748, 1730, nor reaction. At the end of the reaction in 1700. the result of the treatment

NMR (CDCl 3): 3.03, 3.04 (GN, example 12, crude pro-6-OCHj is obtained), 5.12 (2H,), 7.50 (2H, 25 duct, which is purified with, HH using silica gel column

(0.0038 mol) methyl iodide, 1.04 g

Sew for 1 hour. In addition, 0.26 g (0.004 mol) of 85% hydroxide is added to the contents.

f3-NOo /) 8.03 2H, O-NOo /

Example 31. Preparation of 6-0-methyl-2-0.3; -N-bis (benzyloxycarbonyl) -demethyl erythromycin A 9- {jD- (l-- naphthylmethyl) oxime.

4 g (0.0035 mol), 3 - N-bis (benzyloxycarbonyl) -H-demethyl- 35 erythromycin A 9-0 (1-naphthylmethyl) oxime1, are dissolved in 200 ml of H, K-dimethylformamide, with ice cooling, 0.745 g (0.0052 mol) of methyl iodide and 0.254 g (0.0038 mol) of 85% potassium hydroxide in powder form and the mixture is stirred for 2 hours. According to the method of Example 12, the crude obtained in this way product is being cleaned

chromatography (Art.7734, Merck & Co, a mixture of chloroform and acetone in a ratio of 20: 2 as a solvent for elution) to obtain 6.15 g (70.8%) of the title compound as a white foam. Mp 87-7 ° C.

Calculated,%: C, 61.94; H 8.02; N 2.53.

C57H88Ni °

Found,%: C 62.21; H 7.81;

N 2.56.

IR in gus (cm-): 3420, 1745, 1730,

40 170 ° - l

NMR (CDC13) 4: 3.03 (3N, 6-OCH3).

Example 33. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -G} -memethyl erythromycin A 9-G (0 clean and nuidult n.tsei1 c1cl and numbers i ls / from 1

Or (2, /, 2-trichloroethoxymethyl) -oxime.

using silica gel column

chromatography (Wacogel C-200, 1.16 g (0.001 mol) 2-0.3 -N-bis- mixture of ethyl acetate and benzene in ratio- (benzyloxycarbonyl) -H-demethyl erythrocyte 3:10 as solvent (2,2,2-trichloroethoxime- for elution) to obtain 2.21 g of til) oxime1, 342 mg (0.0024 mol) (54.1%) of the target compound, which is 50% methyl iodide and 100 mg, - (0.0015 mol) 85% hydroxide of that isopropyl ether. M.p. 193-195 ° C.

Calculated,%: C, 66.42; H 7.66; N 2.42.55

C64He8N2 ° 17

Found,%: C 66.56; H 7.67; N 2.48.

potassium as a powder in 10 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1: 1 ratio) is stirred together at room temperature for 1.5 hours. The treatment of example 1 gives a crude product, which is then subjected to

22 (cm-): 3360, 1755, 1733,

 My

(O, O 6 mol) 85% potassium hydroxide in powder form and the mixture mixed in powder and the mixture is stirred for h to carry out (0.0038 mol) methyl iodide, 1.04 g

(O, O 6 mol) 85% potassium hydroxide in powder form and the mixture mixed in powder and the mixture is stirred for an hour to effect for 1 hour. In addition, 0.26 is added to the contents. g (0,004 mol) of 85% hydroxide of oxide

chromatography (Art.7734, Merck & Co., 20: 2 mixture of chloroform and acetone as solvent for elution) to obtain 6.15 g (70.8%) of the title compound as a white foam. Mp 87-7 ° C.

Calculated,%: C, 61.94; H 8.02; N 2.53.

C57H88Ni °

Found,%: C 62.21; H 7.81;

N 2.56.

IR in gus (cm-): 3420, 1745, 1730,

170 ° - l

 1.16 g (0.001 mol) 2-0.3 -N-bis- (benzyloxycarbonyl) -H-demethylethyrythromycin A (2,2,2-trichloroethoxymethyl) oxime1, 342 mg (0.0024 mol) iodide methyl and 100 mg (0,0015 mol) of 85% hydroxide

potassium as a powder in 10 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1: 1 ratio) is stirred together at room temperature for 1.5 hours. The treatment of example 1 gives a crude product, which is then subjected to

purification using silica gel column chromatography (Bakogel C-200, a mixture of benzene and acetone in a ratio of 50: 1-10: 1 as a solvent for elution) and recrystallized from a mixture of acetone and n-hexane to obtain 860 mg (37.5 %) of the title compound as prismatic particles. M.p. 1101 3 ° C.

Calculated,%: C 57.07; H 7.10; N 2.38.

Cs6n63Cl, N20,8

Found,%: C 57.32; H 6.82; N2,41.

Ik U maxim): 3400, 1750, 1733, 1728, 1685.

Example 34. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -Y-demethyl-erythromycin A 9-o- (benzyloxymethyl) oxime.

In 100 ml of a mixture of DMZO and tetrahydrofuran (1: 1 ratio) solution 10

15

20

Siloxim D (another oxime isomer of the title compound from Example 18).

In 1.2 ml of a mixture of DMZO and tetrahydrofuran (1: 1), 130 mg (0.00012 mol) of 2-0.3 -H-bis (benzyloxycarbonyl) -M-demethylerythromycin A 9 are reacted. -H-benzyloxime, obtained in Example 9 (another oxime isomer of the target compound from Example 5), 25 mg (0.00018 mol) of methyl iodide and 10 mg (0.00015 mol) of 85% potassium hydroxide as powder technology similar to that of example 12. As a result of processing and subsequent purification using silica gel column chromatography (Wacogel C-200, a mixture of ethyl acetate and l-hexane ratio of 1: 1 as eluant) afforded 102 mg (77.5%) of the title compound as a white foam.

NMR (CDC1,) Ј: 34.6 (C8),

12.9 g (0.015 mol) 2-0.3 -N-bis- 25 187.2 (C), 33.0 (C), 19.7 (8-CH3),

are

(Benzyloxycarbonyl) -M-demethyl-erythromycin A 9-TO- (benzyloxymethyl-toxicum), 3.92 g (0.028 mol) of methyl iodide and 1.14 g (0.017 mol) of 85% potassium hydroxide in the form of powder and the mixture is stirred at room temperature for 40 minutes to carry out the reaction. After completion of the reactions, the treatment in Example 12 gives a crude product, which is then purified using silica gel column chromatography (Wacogel C-200, a mixture of benzene and acetone in a ratio of 100: 1-12.5: 1 as elution solvent) and recrystallized from a mixture of isopropyl ether and n-hexane to give 9.35 g (71.6%) of the desired compound as.

thirty

35

40

45

11.4 (10-CH,). M.p. 94-99 ° C.

Example 36. Preparation of 6-0-methyl erythromycin A 9 (0-methyloxime) -2- (3,4,5-trimethoxybenzoate).

580 mg (0.0006 mol) of erythromycin A 9- (0-methyloxime) -2 - (3,4,5-trimethoxybenzoate) is dissolved in 6 ml of a mixture of DMZO and 1,2-dimethyloxyethane (in the ratio 1: 1). ), 136.8 g (0.00096 mol) of methyl iodide and 66 mg (0.001 mol) of 85% potassium hydroxide in powder form are added to the contents and the mixture is stirred at room temperature for 2 hours to carry out the reaction. After completion of the reaction, 2 ml of triethylamine are added to the contents and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.

crystals

ir "w

(cm- ):

3550-3370, 1745,

About Max 1725, 1695.

NMR (AHSC) fr: 3.05 (3N, 6-OCH3). M.p. 135-136 ° C.

Calculated,%: C 64.12; H 7.80; N 2.46.

Found,%: C 64.41; H 7.61;

N 2.49.

Example 35. Preparation of 6-0-methyl-2-0.3 -N-bis (benzyloxycarbonyl) -H-demethylerythromycin A

0

Siloxim D (another oxime isomer of the title compound from Example 18).

In 1.2 ml of a mixture of DMZO and tetrahydrofuran (1: 1), 130 mg (0.00012 mol) of 2-0.3 -H-bis (benzyloxycarbonyl) -M-demethylerythromycin A 9 are reacted. -H-benzyloxime, obtained in Example 9 (another oxime isomer of the target compound from Example 5), 25 mg (0.00018 mol) of methyl iodide and 10 mg (0.00015 mol) of 85% potassium hydroxide as powder technology similar to that of example 12. As a result of processing and subsequent purification using silica gel column chromatography (Wacogel C-200, a mixture of ethyl acetate and l-hexane ratio of 1: 1 as eluant) afforded 102 mg (77.5%) of the title compound as a white foam.

NMR (CDC1,) Ј: 34.6 (C8),

5,187.2 (C), 33.0 (C), 19.7 (8-CH3),

5,187.2 (C), 33.0 (C), 19.7 (8-CH3),

0

five

0

five

0

five

11.4 (10-CH,). M.p. 94-99 ° C.

Example 36. Preparation of 6-0-methyl erythromycin A 9 (0-methyloxime) -2- (3,4,5-trimethoxybenzoate).

580 mg (0.0006 mol) of erythromycin A 9- (0-methyloxime) -2 - (3,4,5-trimethoxybenzoate) is dissolved in 6 ml of a mixture of DMZO and 1,2-dimethyloxyethane (in the ratio 1: 1). ), 136.8 g (0.00096 mol) of methyl iodide and 66 mg (0.001 mol) of 85% potassium hydroxide in powder form are added to the contents and the mixture is stirred at room temperature for 2 hours to carry out the reaction. After completion of the reaction, 2 ml of triethylamine are added to the contents and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.

The solvent is evaporated under reduced pressure, and the crude product obtained in this way is purified using silica gel column chromatography (Art.7734, Merck Co., a mixture of chloroform and acetone in a 4: 1 ratio as elution solvent) to obtain 260 ml (44.2%) of the title compound. M.p. 131-133 ° C.

EXAMPLE 37. Preparation of 6 O-methyl-3-benzyloxycarbonyl-H-demethylerythromycin A 9 (0-benzyloxyma).

335 mg (0.00035 mol) C1-N-benzyloxycarbonyl-C-demethyl-erythromycin A 9- (0-benzyloxyma) are dissolved in 3 ml of a mixture of DM50 and tetrahydrofuran (in a ratio of 1: 1); 75 mg (0.00053 m) of methyl iodide and 29 mg (0.00044 mol) of 85% potassium hydroxide powder are added to the mixture and the mixture is stirred with ice cooling for 1 hour to carry out the reaction. The treatment of Example 12 yields the product and purifies it using silica gel column chromatography (Wacogel C-200, a mixture of benzene and acetone in a 40: 1 ratio as the elution solvent) to obtain 180 mg (152.9%) of the target compound . M.p. 109-114 ° C.

Subsequent application of the chromatographic separation results in 100 mg of 3-N-benzyloxycarbonyl-M-demethylerythromycin A 9- (0-benzyloxime) from the starting material.

Example 38. Preparation of 6-0-methyl-2-0-benzyloxycarbonylerythromycin A 9- (0-benzyloxime).

According to the technology of Example 12, a reaction was performed using 487 mg1 (0.0005 mol) 2 -0-benzyloxycarbonylerythromycin A 9- (0-benzyloxime), 78.1 mg (0.00055 mol) of methyl iodide and 30.8 mg (0.0004 mol) of 85% potassium oxide hydrate as a powder in 5 ml of a mixture of DM50 and tetrahydrofuran (1: 1-5: 0.8-3), followed by purification by silica gel column chromatography (Vakogel C-200, ethyl acetate as eluent), thereby obtaining 405 mg (82.0%) of the title compound as a white foam.

1H-NMR (SBS1E) Y: 2.99 (3N, 6-OCH)

Example 39. Preparation of 6-0-methyl-2-0-benzyloxycarbonylerythromy t4HH A 9-0- (orthochlorobenzyl) oxime1.

As a result of the treatment according to Example 38 with the use of 1.007 g (0.001 mol) of 2-0-benzyloxycarbonylerythromycin A 9-Ep- (ortho-chlorobenzyloxime) T, 185 mg (0.0013 mol) of methyl iodide and 84 mg (0.0012 mol) 85% potassium hydroxide in powder form in 10 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (E ratio 1: 1) to accelerate the reaction, followed by

ten

15

20

25

thirty

35 ...

0

five

This gives 855 mg of the title compound as a white foam.

1H-NMR (CDC1,): 2.98 (3N, 6-OCH3).

Getting 6-0-methyl derivatives of erythromycin A.

Example 40. To a solution of 1.4 g (0.001 mol) 6-0-methyl-2 -0, g-M-bis (benzyloxycarbonyl) -H-demethyl-erythromycin A (orthochlorobenzyl) oxime in 45 ml of methanol is added 2 , 85 g of I0% palladium carbon, 6 ml (0.16 mol) of formic acid and 1 g (0.015 mol) of formic sodium and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the catalyst is filtered off. Water is added to the filtrate and the pH of the resulting solution is adjusted to approximately 10 with an aqueous solution of sodium hydroxide. The crystals thus obtained are filtered off, washed with water, dried and recrystallized from ethanol to give 5.6 g (75.6%) of 6-0-methyl-M-demethylerythromycin A sim. M.p. 247-249 ° C.

Calculated,%: C 59.34; H 9.15; N 3.74.

C, 7H68N20.3

Found,%: C 59.35; H 8.87 ;, N, 3.78.

Example 41. In a mixture of 12 ml of water, 2 g (0.0027 mol) of 6-0-methyl-M-demethyrrnthromycin A 9-oxyma and 2.25 g (0.02 mol) of sodium sulfate are dissolved. the solution is heated under reflux for 5 hours. After completion of the reaction, the reaction solution is poured into water, the pH of the solution is adjusted to approximately 10 with an aqueous solution of sodium carbonate. The mixture is extracted with dichloromethane and the dichloromethane layer is washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from a mixture of chloroform and diethyl ether to obtain 1.22 g (62.2%) 6-0 -methyldemethyl erythromycin A. T. pl. 217-219 ° C.

Example 42. To a solution of 0.4 g (0.0005 mol) of 6-0-methyl-N-demethyl-erythromycin A in 50 ml of methanol was added 0.2 g of 5% palladium-carbon and 0.4 ml (0.005 mol) of a 37% aqueous formaldehyde solution and the mixture is stirred at room temperature.

Work in a hydrogen atmosphere for 5 hours. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. 50 ml of water are added to the residue, the pH of the solution is adjusted to 10-10.3 with a dilute aqueous solution of sodium hydroxide and the solution is extracted with dichloromethane. The dichloromethane layer is washed with water, dried over anhydrous magnesium sulphate and concentrated. The obtained crystals are recrystallized from ethanol to obtain 0.37 g (90.2%) of 6-0-megylerythromycin A. T. pl. 223-225 S. Ik U yaks (): 3500-3400, 2960-2870, 2820, 2770, 1735, 1690, 1456, 1378, 1168.

Mass (FD) Y m / h 748 (). NMR (CDCl 3) (400 mNh): 3.04, 34.6 (-OCHe), 3.33 (3N, 3 -OCH3). With NMR (CDC1.3): 50.7 (b-och,). Example 43 (by a known method).

To a solution of 6 g of 2-0.3 -Y-bis (benzyloxycarbonyl) -K-demethylerythromycinine A in 30 ml of the system of dry dimethylsulfoxide-tetrahydrofuran (1: 2) is added 3.6 ml of methyl iodide at (-10) - () ° C.

576 mg of a 50% sodium hydride oil suspension are added to the cooled reaction mixture with stirring, then the resulting mixture is stirred for 1 hour at (-10) - (-12) ° C. To the reaction mixture was added 2 ml of triethylamine at 0 - (-5) ° C. After stirring for 2 hours, the mixture was poured into a mixture of 150 ml of ethyl acetate and 50 ml of saturated brine.

After stirring, the organic layer is separated, washed twice with 50 ml of saturated brine, dried over anhydrous magnesium sulfate, evaporated, and dried under vacuum to obtain a white foam. Analysis by liquid chromatography under high pressure shows that the resulting white foam contains products in the following ratio 6-0-methyl derivative: 6,11-di-0 methyl derivative, 6,12-di-O-methyl derivative, 6,4-di- 0th methyl derivative; 1 0-0-methyl derivative; source reagent and other products 34: 13: 2: traces:: 49: traces: traces.

Condition chromatography: silica gel column (Merck silicagel GO, ZO

five

to

IS

20

25

thirty

35

230mesh) using a mixture of ethyl acetate and n-hexane (1: 2) as eluent. Thin layer chromatography: (Herck silicagel GO, F254) layer thickness 0.25 ml, a mixture of ethyl acetate and n-hexane (1: 1) as a solvent at room temperature indicates the presence of a fraction having R. 0.16 (while R 0.07 for the starting material). The fractions having RJ 0.16 are collected and evaporated in vacuo to give 2.85 g (46.8%) of b-O-methyl-2 -0.3 -N-bis (benzyloxycarbonyl) -P-demethylerythromycin A in the form of a white foam (purity for high pressure LC is 65%).

For comparison, it should be noted that the product obtained in Example 22, analyzed in a similar way, has the following characteristics: 6-0-methyl-derivative ratio: 6,11-di-0-methyl derivative: 6,12-di-O-methyl derivative: 6.4 to di 0-methyl derivative: 11-0-methyl derivative: raw material and other products are respectively 80: 7: wake: 2: 1: 8: traces.

Thus, the use of new 9-oxime derivatives allows to increase the selectivity of 6-0-methyl derivatives of erythromycin A.

Claims (1)

Invention Formula The method of obtaining the 9-oxime derivatives of erythromycin A of the general formula NZSN5S20. CH3 "-Of  osnz adyssnz CH3 (I)  sh3 he H3CO CH3 about where R is a lower C -Cj-alkyl, benzyl group, unsubstituted or substituted by methoxy group, nitro group, one or two halogen atoms, naphmethyl group, methylthiomethylaminus group, 1,2,2-trichloroethoxymethyl group, benzyloxymethyl group, benzhydryl group; R, is a hydrogen atom or a benzyloxycarbonyl group; Ke is a methyl or benzyloxycarbonyl group, when uelong that R4 is not a hydrogen atom, when R3 is methyl, R (X where P has the indicated meanings; X - halogen atom 5 in the presence of potassium hydroxide or sodium or sodium hydride, the molar ratio of the compound of general formula III: halogen derivative IV: potassium hydroxide or sodium, or hydride erythromycin derivatives of general formula, / 1 To Lch, n "-, well, 0 sodium is I: (1,08-2,0) :( 0, characterized in that ly 9nz Rio CH3 (Ii) OSSN CHJ CIS ° sleep H3CO CH3 where R2 and R3 have the indicated meanings, are hydroxyl-amine oximated in the presence of imidazole, the molar ratio erythromycin A derivative of general formula 11: hydroxyamine imidimol is 1: 5: 5.5, in methanol at room temperature for 2 days derived derivative of general formula -1.5) in acetone or tetrahydroforming or dimethylformamide with f5 20 25 thirty From 15 ° C to room temperature for 15 minutes to 2 hours, the resulting substituted erythromycin 9-oxime of the general formula N / sn3 RS CHY6 About OvCHa Hgon H3CO CH3 (V) where R (, RZ, 1C have the indicated values, where R2 and R3 have the indicated meanings, are reacted with a halogen compound of the general formula R (X (Iv) -1.5) in acetone or tetrahydroforming or dimethylformamide at that From 15 ° C to room temperature for 15 minutes to 2 hours, the resulting substituted erythromycin 9-oxime of the general formula 20 N / sn3 RS CHY6 About OvCHa Hgon H3CO CH3 (V) thirty 35 ) 40 45 where R (, RZ, 1C have the indicated values, reacted with methyl iodide or dimethyl sulfate in the presence of powdered potassium hydroxide or sodium, the molar ratio of the compound of general formula V: methyl iodide or dimethyl sulfate: powdered potassium hydroxide or sodium hydroxide, or sodium hydride is 1: 1 5:: 0, in the solvent medium such as a mixture of dimethyl sulfoxide and tetrahydrofuran, either dimethyl sulfoxide and 1,2-dimethoxyethane, or dimethylformamide at a temperature from 0 ° C to room for 40 minutes to 5 hours.